Sca-2 is a member of the LY-6 family, a group of small cysteine rich proteins which are widely expressed on the surface of lymphoid cells. These proteins are anchored to the cell membrane by a glycosylphosphotidyl-inositol (GPI) moiety and show conserved protein sequence important for tertiary structure. The general structure seen within the LY-6 family resembles that of the receptor for a urokinase-type plasminogen activator and the alpha-neurotoxins isolated from snake venoms (Fleming T J et al (1993) J Immunol 150:5379-90; Ploug M and V Ellis (1994) FEBS Lett 349:163-8).
Intrathymic T cell precursors express Sca-2. In fact, the progeny of the intrathymic precursor cells continue to express Sca-2 until they transition from blast cells to small cells. During this transition, expression of Sca-2 is downregulated. In contrast, Sca-2 is not expressed on the hematopoietic stem cells of the bone marrow which give rise to T cell precursors or on mature thymocytes and peripheral T cells; however, peripheral B cells are Sca-2 positive.
In studies involving interferon gamma induced murine kidney, Blake P G et al. (1993; J Am Soc Nephrol 4:1140-50) showed a high level of expression of LY-6s associated with lupus nephritis. Such expression makes these molecules either candidates or targets for alloresponses and autoimmune disease. Upregulation of LY-6 was also associated with mercuric chloride nephropathy.
Sca-2 is also related to the mouse thymocyte marker, TSA-1 (Godfrey D I et al. (1992) J Immunol 148:2006-11). TSA-1 is expressed on immature thymocytes and a subset of thymic medullary epithelial cells and appears to be a unique molecule for discriminating between mature and immature thymocytes. TSA-1 is distinct from CD5, CD11a/18, Thy-1, LY6A/E, LY6C, ThB, CD25, and CD44. TSA-1 appears to play a role during positive selection in the transition from CD4+CD8+ thymocytes to the mature CD4+CD8- and CD4-CD8+ subsets (MacNeil I et al. (1993) J Immunol 151:6913-23).
Katz et al(1994; Int J Cancer 59:684-91) showed that LY-6 is highly expressed on non-lymphoid tumor cells originating from a variety of tissues in mice. Upregulation or high expression is correlated with a more malignant phenotype which results in higher efficiency of local tumor production. Since cells with high or low expression show no differences in vitro, it is suggested that micro-environmental factors operating in vivo contribute to malignant phenotype. Katz also noted that antibodies to LY-6 transduce proliferation.
LY-6 proteins also block interleukin 2 (IL-2) secretion (Fleming T J and T R Malek (1994) J Immunol 153:1955-62). IL-2 is an approved anticancer agent and key regulatory hormone in cell-mediated immunity. It stimulates the proliferation of both T and natural killer cells and activates NK cells. In vitro, activated NK cells can directly lyse freshly isolated, solid tumor cells. Fleming also reported that controlled administration of high doses of IL-2 and autologous NK cells (expanded ex vivo) produced favorable responses in patients with metastatic melanoma and renal cell carcinoma.
Understanding the correlations among high expression of Ly-6 family proteins, blocking of IL-2 secretion, and alloresponses or malignancy may allow new approaches to transplantation and treating carcinomas. Identification of novel stem cell antigens provides increased opportunities to develop the diagnostic and pharmacological tools and drugs to intervene in autoimmune diseases, problems arising with allografts and tumor development.